Hematopoietic stem cell (HSC) transplantation (HSCT) is an effective treatment for patients with blood disorders or after radiation injury from a nuclear accident or terrorist attack. Total body irradiation (TBI) has been an indispensable component in a variety of host conditioning regimens for HSCT. However, it is known that ionizing radiation exerts bystander effects on non-targeted cells and that transplanted HSCs suffer from proliferative exhaustion in irradiated recipients. Moreover, our own preliminary study documented a negative proliferation-independent bystander effect of the TBI- conditioned mouse recipients on transplanted HSCs. Therefore, efficacy of HSCT is determined by not only donor HSCs but also host conditions. In this application, we plan to: 1) further quantify the negative bystander effects of irradiated bone marrow on transplanted HSCs at different time points upon transplantation in the hosts that will be conditioned with different doses of gamma irradiation; 2) then examine specific cellular and molecular mechanisms underlying the negative effect; and 3) finally explore the beneficial effects of several anti-oxidative agents in HSCT. Results from our current proposed study will yield novel strategies for enhancing the engraftment efficiency of transplanted HSCs in irradiated recipients. Abstract: Hematopoietic stem cell (HSC) transplantation (HSCT) is an effective treatment for patients with blood disorders or after radiation injury from a nuclear accident or terrorist attack. In this study, we are going to study how irradiated hosts may negatively impact the transplanted HSCs. Results from our proposed studies will yield novel strategies for enhancing the engraftment efficiency of transplanted HSCs in irradiated recipients.